Depletion of Fumarate hydratase in tumor cells causes an accumulation of fumarate in the TME, which directly succinates ZAP70 at C96 and C102 and effectively blocks the phosphorylation of the ZAP70 substrate LAT as well as the downstream TCR signaling pathway, leading to suppressed CD8+ T cell activation and reduced IFN-γ, TNF-α and GZMB production [301]. This evidence concerns the gene CD8A and neoplasm.